Some benzyl-substituted imidazoles, triazoles, tetrazoles, pyridinethiones, and structural relatives as multisubstrate inhibitors of dopamine beta-hydroxylase. 4. Structure-activity relationships at the copper binding site.
Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1) by examining the effects upon in vitro inhibitory potencies resulting from structural changes at the copper-binding region of inhibitor. Attempts were made to determine replacement groups for the thione sulfur atom of the prototypical inhibitor 1-(4-hydroxybenzyl)imidazole-2-thione described previously. The synthesis and evaluation of oxygen and nitrogen analogues of the soft thione group demonstrated the sulfur atom to be necessary for optimal activity. An additional series of imidazole-2-thione relatives was prepared in an effort to probe the relationship between the pKa of the ligand group and inhibitory potency. In vitro inhibitory potency was shown not to correlate with ligand pKa over a range of approximately 10 pKa units, and a rationale for this is advanced. Additional ligand modifications were prepared in order to explore bulk tolerance at the enzyme oxygen binding site and to determine the effects of substituting a six-membered ligand group for the five-membered imidazole-2-thione ligand.
Kruse
L I
LI
Research and Development Division, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
Kaiser
C
C
DeWolf
W E
WE
Finkelstein
J A
JA
Frazee
J S
JS
Hilbert
E L
EL
Ross
S T
ST
Flaim
K E
KE
Sawyer
J L
JL
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D003300:Copper / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology; D013871:Thiones / Q000138:chemical synthesis / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D013777:Tetrazoles; D013871:Thiones; D014230:Triazoles; D003300:Copper; D004299:Dopamine beta-Hydroxylase